Without limiting the scope of the invention, its background is described in connection with ion exchange resins, as an example. Currently, ion exchange resins used in pharmaceutical applications serve a variety of functions, e.g., providing sustained-release, masking tastes, eliminating polymorphism, improving the dissolution of poorly soluble drugs, eliminating deliquescence, reducing water uptake, improving stability, reducing abuse liability and improving physical characteristics of pharmacologically active drugs. For example, ion exchange resins are used to prolonged the continuous release of pharmacologically active drugs by absorbing the drug to the ionic exchange resin to form a drug-resin complex in which the drug is released over time. In certain instances, a rate controlling coating is applied to the drug-resin complex to prolong the release of the pharmacologically active drug.
The sustained-release drug-resin complex provides a controlled-release of the pharmacologically active drug over a given period of time. Thus, these complexes allow a continuous or intermittent supply of the active drug to a subject. The sustained-release drug-resin complex provides a convenient dosage form that provides a therapeutic drug levels throughout an extended period. The release of the drug maintains a therapeutically effective plasma level significantly longer than that given by a typical drug dosage form.
In a general sense, an ion exchange resin can be described as an assembly of polymers that contain ionizable groups distributed along the polymer backbone. The ionizable groups of the polymer backbone are associated with ions. When the polymer is combined with a solution of counter ions, the counter ions in the solution exchange with the ions of the polymer and the counter ions are physically removed from the solution. Therefore, counter ions (e.g., drug ion) in solution can exchange with the ions of the ion exchange resin (e.g., polymer) through an ionic interaction, as opposed to a covalent interaction. The pharmacologically active drug ions can then be eluted from the ion exchange resin to treat the subject.
A substantial portion of the active drug is ionically bound within the polymer matrix of the ion exchange resin. The active drug elutes from the polymer matrix over time to provide a specific release profile. The size of the adsorbed drug molecule and/or the size of the polymer resin particle (e.g., the cross linkage of the cationic exchange resin) may be altered to control the elution rate. The process of adsorption of a pharmacologically active drug to ion exchange resin is a well-known technique to the skilled artisan and the subject of many United States and foreign patents. Generally, adsorption is accomplished by mixing a pharmacologically active drug and an ion exchange resin in an aqueous solution, filtering, washing, drying and optionally coating the drug-resin complex with a water-permeable diffusion barrier.
For example, U.S. Pat. No. 4,996,047 discloses oral pharmaceutical preparations, which include a pharmacologically active drug bound to an ion-exchange resin to provide a drug-resin complex having a drug content above a specified value. The drug-resin complex is subsequently coated with a water-permeable diffusion barrier coating that is insoluble in gastrointestinal fluids. Thus, the release of drug is controlled under conditions encountered in the gastrointestinal tract.
One of the major disadvantages with the use of an ion exchange resin as a pharmaceutical delivery agent is that ion exchange resin particles are susceptible to swelling. For example, ion exchange resins drug complexes can undergo significant swelling when the dry, non-hydrated drug complex contacts fluids, e.g., water, biological fluids, gastrointestinal fluids. The swelling of the ion exchange resin often ruptures the diffusion barrier coating, which causes a loss of control of the diffusion rate of the drug and alters the drug release profile.
U.S. Pat. No. 4,847,077 (the '077 patent) discloses sulfonic and cationic exchange resins treated with a critical amount of glycerin to enhance their coatability. The specification discloses methods to achieve prolonged continuous release of a pharmacologically active monobasic drug absorbed on a sulfonic acid cationic exchange resin treated with a critical amount of glycerin. Specifically, controlled-release pharmaceutical preparations containing coated sulfonic acid cationic exchange resin drug complex particles are taught, that are treated prior to coating with about 15 to 25% by weight of glycerin.
Finally, U.S. Pat. No. 4,221,778 (the '778 patent) teaches a pharmaceutical preparation containing a diffusion barrier coated ion exchange resin drug complex treated with a solvating agent. The solvating agent retards the rate of swelling in water but does not reduce the overall amount of swelling, only the rate at which swelling occurs. The '778 patent claims a pharmaceutical preparation having ion exchange resin particles with a pharmacologically active drug absorbed thereon to form drug-resin complex particles. The resin particles have been treated with an impregnating agent (e.g., polyethylene glycol, propylene glycol, mannitol, lactose and methylcellulose) in an amount sufficient to retard the rate of swelling in water and subsequently coated with a water-permeable diffusion barrier.